title: Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists.
abstract: Immunogenic cell death induced by anticancer chemotherapy is characterized by a series of molecular hallmarks that include the exodus of high-mobility group box 1 protein (HMGB1) from dying cells. HMGB1 is a nuclear nonhistone chromatin-binding protein. It is secreted at the late stages of cellular demise and engages Toll-like receptor4 (TLR4) on dendritic cells (DCs) to accelerate the processing of phagocytic cargo in the DC and to facilitate antigen presentation by DC to T cells. The absence of HMGB1 expression by dying tumor cells exposed to anthracyclines or oxaliplatin compromises DC-dependent T-cell priming by tumor-associated antigens. Here, we show that transplantable tumors exhibiting weak expression of nuclear HMGB1 respond to chemotherapy more effectively if the treatment is combined with the local or systemic administration of a highly purified and physiochemically defined and standardized lipopolysaccharide solution, which acts as a high-potency and exclusive TLR4 agonist, called Dendrophilin (DEN). The synergistic antitumor effects mediated by the combination of chemotherapy and immunotherapy relied upon the presence of the MyD88 (myeloid differentiation primary response gene) adapter of TLR4 (but not that of the TIR-domain-containing adapter-inducing interferon-β adapter), in line with the well-characterized action of DEN on the MyD88 signaling pathway. DEN and anthracyclines synergized to induce intratumoral accumulation of interferon-γ-producing CD4(+) and CD8(+) T lymphocytes. Moreover, DEN could restore the immunogenicity of dying tumor cells from which HMGB1 had been depleted by RNA interference. These findings underscore the potential clinical utility of combination regimens involving immunogenic chemotherapy and certain TLR4 agonists in advanced HMGB1-deficient cancers.
authors.affiliation: 1] INSERM U1015, Villejuif, France [2] Institut de Cancérologie Gustave Roussy, Villejuif, France [3] University of Paris Sud XI, Villejuif, France.
authors.forename: T
authors.initials: T
authors.lastname: Yamazaki
authors.forename: D
authors.initials: D
authors.lastname: Hannani
authors.forename: V
authors.initials: V
authors.lastname: Poirier-Colame
authors.forename: S
authors.initials: S
authors.lastname: Ladoire
authors.forename: C
authors.initials: C
authors.lastname: Locher
authors.forename: A
authors.initials: A
authors.lastname: Sistigu
authors.forename: N
authors.initials: N
authors.lastname: Prada
authors.forename: S
authors.initials: S
authors.lastname: Adjemian
authors.forename: J P P
authors.initials: JP
authors.lastname: Catani
authors.forename: M
authors.initials: M
authors.lastname: Freudenberg
authors.forename: C
authors.initials: C
authors.lastname: Galanos
authors.forename: F
authors.initials: F
authors.lastname: André
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: L
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000627:therapeutic use / Q000633:toxicity; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D016923:Cell Death / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D008070:Lipopolysaccharides / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000401:mortality / Q000628:therapy; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000378:metabolism
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4